Respiratory syncitial virus (RSV)-associated bronchiolitis is the leading cause of childhood hospitalization worldwide. However, the development of specific therapies is limited by poor understanding of disease pathogenesis. Investigators have reported associations between severe RSV bronchiolitis and high virus titers, reduced inflammation, type 2 helper T cell (TH2) bias, and specific TLR4 variants; however, others have failed to replicate these findings. Now, Caballero et al. convincingly address these controversies in a large prospective, case-control study that includes distinct cohorts for discovery and validation.

Both cohorts included approximately 400 healthy, term infants diagnosed with mild (40%) or severe (60%) RSV bronchiolitis. The subjects lived either in rural (poor) or urban (rich) areas near Buenos Aires, Argentina. The first key finding of this study is that environmental lipopolysaccharide (LPS) levels, measured on bed sheets, were highest in rural areas. LPS are endotoxins produced by bacteria that stimulate the immune system by activating TLR4. High LPS levels were strongly correlated with nasal carriage of multiple bacterial strains. Two groups of children at high-risk for severe RSV infection were identified in both discovery and validation cohorts: rural children exposed to high LPS level with wild-type TLR4 genotypes, and urban children exposed to low LPS levels with heterozygous TLR4 variants.

Nasal secretion testing failed to reveal associations between disease severity and RSV titers, RSV strains, or levels of inflammatory markers [interleukin-6 (IL-6), IL-8, IL-β, and tumor necrosis factor–α (TNF-α)]. High IL-6 and IL-8 levels were instead strongly correlated with low LPS exposure. However, two lines of evidence support a role for TH2 bias in triggering severe disease: high ratios of GATA3/Tbet mRNAs and high ratios of IL-4/IFN-γ levels. Transcription factor GATA3 promotes T cell differentiation to TH2 cells, which secrete IL-4.

These data, which will need to be replicated independently, suggest that at least in some infants, the interaction between TLR4 genotypes and environmental triggers cause an exaggerated TH2 response during RSV infections. Experiments performed in relevant mouse models recapitulated most of these findings, which is promising for future investigations. However, these observations must be only the tip of the “pathophysiologic iceberg”—most patients with severe RSV bronchiolitis did not fit the patterns identified.